Sorafenib Concurrent With Yttrium-90 Transarterial Radioembolization in Patients With Advanced Hepatocellular Cancer

Studies in Asia of unresectable hepatocellular cancer (HCC) demonstrated that sorafenib could
be administered safely at 400mg twice a day (BID) when initiated 14 days following
radioembolization (RE). However, the ideal sequence of RE and sorafenib may not be completely
elucidated, the two treatments given concurrently may be more effective than the sequential
approach studied in the Asian trials. Preclinical models have demonstrated that sorafenib
acts synergistically with radiation, increasing apoptosis. Furthermore, case reports suggest
profound responses in patients who have received sorafenib concurrent with transarterial
radioembolizatoin (TARE) as evidenced by improvement in symptoms, >80% decrease in alpha
fetoprotein (AFP), and conversion from unresectable to resectable. Sorafenib concurrent with
TARE may take advantage of the synergistic relationship between the two therapies and prove
to be a more effective treatment strategy than sequential administration of TARE and
sorafenib.

Inclusion Criteria:

- Histologically or cytologically confirmed HCC or clinical diagnosis by American
Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic subjects is
required. m)

- Barcelona Clinic Liver Cancer Stage B or C. Segmental and subsegmental portal vein
thrombosis is allowed.

- Metastatic disease is allowed if investigator feels liver directed therapy could offer
palliative benefit (i.e., minimal extrahepatic tumor burden)

- No evidence of cirrhosis or cirrhosis grade of Child-Pugh class A or B7. Eligibility

- Have at least one tumor lesion that can be accurately measured according to Response
Evaluation Criteria in Solid Tumor (RECIST v1.1).

- Consultation with interventional radiologist and deemed an appropriate candidate for
TARE.

- Prior local therapy, such as surgery, hepatic arterial embolization,
chemoembolization, radiofrequency ablation, percutaneous ethanol injection or
cryoablation is allowed if the index lesion(s) remains outside of the treatment field
or has progressed since prior treatment. Local therapy must have been completed at
least 4 weeks prior to the baseline scan.

- Prior yittrium-90 transarterial radioembolization (TARE) or sorafenib not allowed

- Patient must be informed of the investigational nature of this study, sign and give
written informed consent in accordance with institutional and federal guidelines.

- Age ≥ 18 years.

- Eastern Cooperative Group (ECOG) performance status ≤ 1.

- Have adequate hematologic function as documented by an absolute neutrophil count (ANC)
≥ 1000/ul, platelet count ≥ 60,000/ul, and hemoglobin ≥ 8.5 mg/dl obtained within 28
days prior to registration.

- Have adequate hepatic function, as determined by the following tests measured within
28 days prior to registration: serum bilirubin ≤ 2 x upper limit of normal (ULN);
serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate
transaminase (SGPT) ≤ 5 x the institutional upper limit of normal (IULN).

- Have adequate renal function, as determined by the following tests measured within 28
days prior to registration: serum creatinine ≤ 1.5 x ULN OR a measured creatinine
clearance or calculated creatinine clearance ≥ 50 mL/min.

- Have a life expectancy of ≥12 weeks

- Must be able to swallow oral medications.

- Negative pregnancy test done ≤7 days prior to registration, for women of childbearing
potential only.

Exclusion Criteria:

- Known or suspected allergy or hypersensitivity to sorafenib.

- Any malabsorption condition.

- Must not have known brain metastases.

- No concurrent anticancer chemotherapy or local therapy.

- No concurrent herbal or unconventional therapy (e.g., St. John's Wort)

- Pregnant or nursing women

- No prior radiation therapy to the liver

- Inability to perform y90 TARE due to: (1) inability to catheterize the hepatic artery,
(2) portal vein thrombosis/occlusion without the ability to perform selective
infusion, (3) Tecnetium-99m macro-aggregated albumin hepatic artery perfusion
scintigraphy shows unfavorable shunt fraction between the liver and the pulmonary
parenchyma as determined by the interventional radiologist, or (4) other
contraindication to TARE identified by interventional radiologist.

- Women/men of reproductive potential unwilling or unable to use an effective
contraceptive method

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
Stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease-free for 3 years.

- History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic
conduction abnormality within 6 months.

- Concurrent severe or uncontrolled medical disease (i.e., active systemic infection,
diabetes, coronary artery disease, congestive heart failure) that, in the opinion of
the Investigator, would compromise the safety of the patient or compromise the ability
of the patient to complete the study.